The proposed project is designed to study the interactions of glucagon and insulin on liver glucose production and glucose disposal in man and the role of glucagon in the development of diabetic hyperglycemia. The unique experimental techniques employed in this study (e.g., insulin clamp, 3-3H-glucose, physiological hormone infusions, kinetic modelling) will provide quantitation of: (1) the effects of the physiologic increments (and decrements) in glucagon and insulin on glucose metabolism; (2) the effect of physiologic hyperglucagonemia on insulin resistance; and (3) glucagon turnover in diabetes. These studies will also examine the mechanism of the evanescent effect of hyperglucagonemia on hepatic glucose production. The proposed project is of particular interest regarding the potential therapeutic benefit of glucagon-inhibitory agents (somatostatin) in diabetes. He will examine the effect of prolonged somatostatin administration in diabetics with and without residual insulin secretion and the contribution of glucagon to the magnitude of the hyperglycemia induced by insulin deficiency. Furthermore, the effect of somatostatin on intestinal glucose absorption and potassium handling will be evaluated to determine possible nutritional and metabolic hazards of this drug. Finally we will evaluate the usefullness of somatostatin as an investigational tool in the study of insulin-glucagon interactions in glucose homeostasis. This project will thus provide important data regarding the pathogenesis and pathophysiology of diabetes and the usefullness of somatostatin in the treatment of diabetic man.